Abstract 5070: Pitavastatin Has Anti-atherosclerotic Effects via Inhibition of TRAIL Expression on CD4 T Cells
Background: Statins reduce cardiovascular-related morbidity and mortality, however their effects on inflammation in atherosclerosis are not fully understood. We investigated whether pitavastatin can modulate cytotoxic functions of CD4 T cells in acute coronary syndrome (ACS) and inhibit the development of atherosclerosis in apoE deficient mice (apoE KO).
Methods and Results: Fresh CD4 T cells were isolated from blood obtained from 37 patients with ACS without statin treatment on admission and 34 control patients. CD4 T cells derived from ACS patients effectively induced vascular endothelial cell (EC) apoptosis significantly more than controls (P<0.0001). CD4 T cells from ACS patients expressed higher levels of TRAIL (P<0.002) than those of controls. We further examined whether statin could regulate TRAIL expression and cytotoxicity of CD4 T cells. Pitavastatin (PIT, 10μM) blocked CD4 T cell-mediated EC apoptosis (P=0.001) and reduced the expression of TRAIL (P<0.01) on CD4 T cells from ACS patients. Finally, to investigate whether TRAIL-expressing CD4 T cells had biological relevance in vivo, 12-week-old ApoE-deficient mice were fed a high-fat diet supplemented with 1mg/kg/day PIT (n= 5), 10mg/kg/day (n= 5), or Vehicle (0.5% carboxy-methyl cellulose, n= 5) for 8 weeks. Sudan IV staining of the aorta and oil red O-staining of the aortic sinus revealed that 1mg/kg/day and 10mg/kg/day PIT significantly suppressed the development of atherosclerotic lesions depending on dose (P<0.05, P<0.0001, respectively). In addition, PIT suppressed inflammatory infiltrates and CD4 T cells in atherosclerotic plaque by immunohistochemistry. Furthermore, to investigate whether PIT inhibited the expression of TRAIL on CD4 T cells, CD4 T cells were isolated from spleen and analyzed by FACS. The expression of TRAIL was significantly inhibited by 1mg/kg/day and 10mg/kg/day PIT (P<0.01, P<0.005, respectively).
Conclusions: TRAIL-expressing CD4 T cells are enriched in ACS patients and apoE deficient mice and induce endothelial injury, which may contribute to the increasing plaque instability. Pitavastatin therapy may prevent T cell-mediated endothelial cell damage and contribute to the prevention of atherosclerotic plaque development and plaque instability.